A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3

Robert C. Kaplan, Ann Kristin Petersen, Ming Huei Chen, Alexander Teumer, Nicole L. Glazer, Angela DÖring, Carolyn S.P. Lam, Nele Friedrich, Anne Newman, Martina Müller, Qiong Yang, Georg Homuth, Anne Cappola, Norman Klopp, Holly Smith, Florian Ernst, Bruce M. Psaty, H. Erich Wichmann, Douglas B. Sawyer, Reiner BiffarJerome I. Rotter, Christian Gieger, Lisa S. Sullivan, Henry Völzke, Kenneth Rice, Ariadni Spyroglou, Heyo K. Kroemer, Y. D. Ida Chen, Jenny Manolopoulou, Matthias Nauck, Howard D. Strickler, Mark O. Goodarzi, Martin Reincke, Michael N. Pollak, Martin Bidlingmaier, Ramachandran S. Vasan, Henri Wallaschofski

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 3 10 -8 (P = 3.3 × 10 -101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10 -26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10 -21) and higher IGF-I (P = 4.9 × 10 -9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10 -11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10 -10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10 -7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

Original languageEnglish (US)
Article numberddq560
Pages (from-to)1241-1251
Number of pages11
JournalHuman molecular genetics
Volume20
Issue number6
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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